Mineral and Metal Neurotoxicology, ed. M. Yasui, M .J. Strong, K. Ota, & M. A. Verity, CRC Press: Boca Raton, New York, London, Tokyo, 1997
Whatever the age, nervous forms of magnesium deficit represent the most commonly seen form in clinical practice.1 First of all, it seems very important to discriminate between the two types of magnesium deficit: magnesium deficiency and magnesium depletion. In the case of magnesium deficiency, the disorder corresponds to an insufficient magnesium intake: it merely requires oral physiological magnesium supplementation. In the case of magnesium depletion the disorder which induces magnesium deficit is related to a dysregulation of the control mechanisms of magnesium metabolism, either failure of the mechanisms which insure magnesium homeostasis or intervention of endogenous or iatrogenic perturbating factors of the magnesium status. Magnesium depletion requires more or less specific correction of its causal dysregulation.1 It should not be permitted today to extrapolate from physiological data observed in overt acute magnesium deficiency to physiological consequences of chronic magnesium deficiency. Although acute and chronic magnesium deficiencies are specifically reversible through oral magnesium supplementation with physiological doses, the experimental and clinical symptoms may differ. The typical pattern of chronic magnesium deficiency is latent whereas overt signs are observed in acute magnesium deficiency. The discrepancy between the patent and latent nervous forms of magnesium deficiency suggests that in the latent form there are compensatory factors which antagonize the nervous hyperexcitability observed in the overt form.
The aim of this review is to study:
We will analyze the mechanisms of action of magnesium deficiency on the nervous system successively through electrophysiological, biochemical, and clinical data.
Experimental and clinical electrophysiological procedures allow us to neurophysiologically examine the effects of magnesium deficiency on the cortical, subcortical, and peripheral levels of the nervous system.
Standard electroencephalography (EEG) in humans exhibits "diffuse irritative tracings" without focal lesions or paroxysmal discharges. The recordings contain spikes, a pointed appearance of alpha and/or theta waves, which is facilitated more often by hyperventilation than by intermittent photic stimulation. The polygraphic study of afternoon sleep may complete the data of standard EEG: brevity of the time required to fall asleep, superficial character of the sleep, frequency of awakening, hypnoagnosia.1 The EEG in the magnesium-deficient rat (electrocorticography) allows us to make observations similar to those found in humans. Mg deficiency induces electrocorticographic alterations in the rat analogous with those seen in Mg deficiency in humans. Sleep quality analysis shows particularly similar alterations of the hypnograms.1,2
Electronystagmography shows functional impairment at the level of the second vestibulo-ocular motoneuron which becomes apparent mainly as the variable association of "paroxysmal ocular states", i.e., a sequence of repetitive ocular movements with vertical predominance over a period averaging 20 s, irregularity of evoked nystagmic responses, excessive bilateral labyrinthine reflex activity, oblique or rotary nystagmus, prolonged latency during pendular tests, and differences between pendular nystagmic responses with the eyes open and closed. Alterations in optokinetic tests confirm the importance of subcortical functional disturbances.1
Moreover, behavioral changes in the Mg-deficient rats are due to hyperexcitability which first arises in deeper structures -- in the whole limbic system and in the hippocampus, particularly -- and which secondarily becomes generalized by projecting on the neocortices. 3
Electromyography (EMG) shows peripheral NHE. A series of autorhythmic events is observed (singlets, multiplets, complex tonicoclonic activity) beating for more than 2 min during one (or several) of the three facilitations tests: tourniquet-induced ischemia lasting 10 min, a postischemic phase measured 10 min after removal of the tourniquet, and finally hyperventilation for a maximum of 5 min. A repetitive EMG, whatever the intensity, constitutes the principal neurophysiological mark of NHE due to Mg deficiency.1
Skin conductance reflex might appear attractive as an investigation tool of diffuse NHE due to Mg deficiency,4 but this procedure still requires further validation.
These neurophysiological procedures, mainly EEG, ENG, and EMG, allow us to examine the effects of Mg deficiency on the nervous system: Mg deficiency causes diffuse neuromuscular hyperexcitability operating from the center to the periphery. NHE affects the nervous system as a whole, but comparing the impairments in its various sectors is less important than determining the intra- or extracellular origin of NHE.1,5
The long duration of experimental Mg deficiency required to produce manifestations of NHE has led to the hypothesis of concurrent reduction of intracellular Mg which represents "the bulk" of the Mg pool. In Mg deficiency induced in young rats, there is a direct correlation between the severity of hyperexcitability and the decrease in the brain Mg level. Clinical evidence includes patients with Mg deficiency but without abnormalities of extracellular Mg, hypo- or normomagnesemia in the same patient at different times, and a reduction of the mean erythrocyte or lymphocyte Mg contents, two forms of intracellular Mg. This demonstrates the possible role of intracellular Mg in NHE due to Mg deficiency.
This NHE is not always accompanied by low levels of cerebral Mg: these are only observed in severe Mg deficiency in young rats. Usually, no changes have been found in brain Mg concentrations during the course of Mg deficiency in adult rats.5-7 It should be stressed that in Mg deficiency there exist complex mechanisms to maintain normal, and even increased, Mg concentration in the tissue which are of vital importance in brain, liver, and brown fat.5-8 With reduced plasma Mg levels, an extracellular origin of NHE due to Mg deficiency may intervene, but plasma normomagnesemia has also been observed with some Mg deficiencies.
An analysis of the relationship between extra- and intracellular concentrations, clinical findings, and electronystagmographic tracings have shown that more symptoms of NHE occur when Mg deficiency predominates in one of the intra- or extracellular compartments rather than when it affects both equally.1,5 This electroclinical observation highlights the importance of Mg distribution disturbances in the physiopathological consequences of Mg deficiency on the nervous system.
During Mg deficiency, a complex neuroendocrinometabolic and renal regulation may intervene for compensating its systemic effects. The role of the blood-brain barrier which attenuates the effect of the systemic regulating factors of Mg status and of the humoral consequences of decompensated Mg deficiency in the nervous system must not be overlooked. The biochemical factors capable of increasing nervous excitability are essentially local.1,5
Extrapolating from data observed in vitro, in situ, or in other pharmacological manipulations to the physiological basis of an Mg deficiency simply due to insufficient intake1 remains a methodological error.
Pharmacological Mg excess causes some systemic reactions which are not the opposite of physiological effects of Mg. For example pharmacological load of Mg increases release of calcitonin and nitric oxide (NO).9,10 In contrast, physiological Mg supplementation, far from acting similarly, reduces high levels of calcitonin1 (as well as of calcitonin gene-related peptide11and of NO12 released in the case of Mg deficiency.
The great stability of brain Mg during Mg deficiency particularly disagrees with the very notion of extrapolating from in vitro or in situ, extra- or intracellular Mg data1,5 to in vivo physiological data. This leads to suggesting an updated scheme of the factors which cause NHE5: Mg deficiency would induce a diffuse NHE through a neuronal depolarization which derives from the sum of its direct cellular effects in the neural cells and from several mediated reactions.5
Mg deficiency results in three basic effects: disturbances in cellular Ca distribution, decreased second messenger nucleotidic ratio,5 and increased susceptibility to peroxydation.12-14 Through membranous and postmembranous alterations, Mg deficiency brings about a cellular Ca load with subcellular distribution modifications.5 Mg deficiency reduces 3',5'-cyclic adenosine monophosphate (cAMP) concentration and increases 3',5'-cyclic guanosine monophosphate (cGMP) concentration, perhaps through inhibition of adenylate cyclase and activation of guanylate cyclase.5 Mg-deficient animals show an increased susceptibility to in vivo oxydative stress and the tissues of these animals are more susceptible to in vitro peroxydation, affecting lipid particularly.12-14 Protein oxydation in Mg-deficient rat brains occurs early. A significant increase of protein carbonyls is observed within 2 to 3 weeks of a Mg-deficient diet. These changes take place prior to any detectable tissue damage, dysfunction, or changes in cellular glutathione.15
Mg deficiency may increase formation of free radicals directly, but also indirectly through free-radical-triggered mechanisms.12 ,15
NHE due to Mg deficit is also linked to modifications in the turnover of various types of neurotransmitters: monoamines, amino acids, but also nitric oxide, neuropeptides, and cytokines.
Neurotransmitters - NHE due to Mg deficiency mainly depends on modifications in the turnover of several neuromediators and neuromodulators. They associate an increased turnover of the monoamines: serotonin (5HT), acetylcholine, catecholamines (dopamine and noradrenaline, mainly), and of excitatory amino acids (aspartic and glutamic acids, mainly) with a decreased turnover of inhibitory amino acids (γ-amino butyric acid and taurine, mainly).5 As a great number of in vitro studies on Mg and NMDA16 receptors have suggested that the latter had predominant and almost exclusive importance, their in vivo role has often been overestimated.2 If hyper NMDA receptivity enters into the mechanisms of NHE due to Mg deficiency as confirmed in vivo,17 a hyperreceptivity concerning other non-NMDA receptors of excitatory amino acids may also intervene.18 The genuine complexity of biology must not be disregarded just because the present trend is towards focusing on NMDA receptors at the expense of many other receptors.
Nitric oxide, peptides, and cytokines - An increased production of nitric oxide and of various inflammatory peptides - such as substance P, CGRP, and VIP - is observed in Mg-deficient rats. All these substances might directly intervene as neurotransmitters in the physiopathology of NHE due to Mg deficiency; but NO could also mediate an increase in cGMP whereas inflammatory neuropeptides might stimulate production of inflammatory cytokines and of free radicals.12-14 During the progression of Mg deficiency in a rodent model, dramatic increases of inflammatory cytokines were observed: interleukins 1 and 6 (IL1, IL6) and tumor necrosis factor (α(TNFα ). Increase of these various cytokines was neither concomitant nor constant, according to species and strains.12-14,19 So far, their importance in the physiopathology of NHE has not been clearly defined but we have observed with P. Maurois that audiogenic seizures in Mg-deficient mice might be correlated with possible TNFα release. According to the strains of mice, there is a parallelism between production of TNFα. induced by bacterial lipopolysaccharides and NHE. However, coexistence does not mean causality and further research focusing on the effects of specific TNFα antibody on the production of audiogenic seizures will be necessary. Opioid peptide activity could be reduced since, in the complex mechanisms of opioid action, Mg at the physiological level may be most often an agonist of δ, µ, and κ opioid receptors.5,20
The sum of these direct and mediated local factors may bring about overt NHE due to Mg deficiency. Frequency of latent forms of this NHE postulates the existence of local compensatory factors which may control NHE.5
The local compensatory factors instrumental in the latency of NHE due to Mg deficiency may also be direct and mediated.
Since Mg can more or less be replaced by a natural polyamine in many biochemical reactions, an "Mg-substitutive" increase in polyamines might decrease the direct cellular effects of Mg deficiency. This "Mg-vicariant" increase in polyamines may be a factor regulating the alterations of protein synthesis and particularly that of Ca2+ and Mg2+ binding proteins.5 Increased formation of free radicals may be antagonized by the cell antioxidant system: enzymes such as superoxide dismutase and glutathione peroxidase, antioxidant vitamins such as E, A, and C, selenium, and sulfur compounds such as glutathione and taurine.8, 14-18
Some types of adenylate cyclase-receptors may contribute to a compensatory increase in the cAMP/cGMP ratio.5 The main compensatory factors are mediated by the increase of several physiological neuroprotective agents: inhibitory aminoacids1,5,10,21-23 and perhaps melatonin.24 The particular efficiency of N-acetyl-amino compounds such as Mg N-acetyl-amino taurinate and melatonin might depend on a decreased activity of the Mg-dependent N-acetyl-amino transferase in the nervous system (EC 126.96.36.199.).10,21-24 The main mediated compensatory factor is taurine (TA) with the help of its peptidic congener: γ-L-glutamyl taurine (GTA).5
When these direct and mediated compensatory factors are effective, NHE remains latent. It is patent when compensatory factors are insufficient. Their failure may depend on several reasons:
1 . Sufficient amounts of amino acids - precursors of neuromediators and neuromodulators - must be available in the nervous system. It is important to have qualitatively and quantitatively a sufficient protein intake and sufficient amino acid transport across the blood-brain barrier, eventually facilitated by a homeostatic reactive hyperinsulinism. Both may be lacking.
2. If a compensatory high release of cAMP counteracts the decrease of cAMP/cGMP ratio, it inhibits the TA biosynthesis through the reduction of cystine dioxygenase activity.
3. Efficient brain metabolism and, particularly enzymatic activity, is necessary. However, Mg deficiency frequently alters protein biosynthesis and induces enzymatic hypoactivity.
4. Finally, the number of excitatory factors appears larger than that of compensatory factors during Mg deficiency in the nervous system.5
However, one should not overlook the schematic nature of this general pattern which covers both a homogeneous explanation of the diffuse character of the symptomatic NHE due to Mg deficiency and the possibility of the Mg deficient latent form.
Because of the heterogenicity of NHE due to Mg deficiency, a special study of each parameter of this scheme in each brain area is necessary to obtain a better understanding of these complex phenomena.5
NHE due to Mg deficiency results in a nonspecific clinical pattern which associates peripheral and autonomic neuromuscular signs and central or rather psychiatric symptoms. Neuromuscular disturbances include acroparesthesias, muscle fasciculations, cramps, and myalgias occurring more frequently than tetanoid or tetanic attacks, and various autonomic functional complaints such as cardiac palpitations, precordial pain, extrasystolae, Raynaud's syndrome, hepatobiliary dyskinesia, gastrointestinal cramps and spasms, and asthma-like dyspnea.
Psychiatric symptoms consist of anxiety, hyperemotionality, asthenia, headache, insomnia, dizziness, nervous fits, lipothymias, and sensations of a "lump in the throat" and of "blocked breathing". On encountering this nonspecific pattern, the signs of neuromuscular hyperexcitability are of much greater importance. Chvostek's sign must be sought systematically. The sign is positive in 85% of cases examined. Trousseau's sign, less sensitive than Chvostek's sign, is observed only in cases of obvious hyperexcitability. The hyperventilation test can complete the search for Chvostek's sign and may give greater sensitivity to the Trousseau's sign (Von Bonsdorff's test).
Neurophysiological tracings and routine Mg assessment (at least plasma and red blood cell Mg; if possible evaluation of Mg intake and daily magnesuria, calcemia, and calciuria) may complete the clinical examination. However, the diagnosis of Mg deficiency mainly requires an Mg oral loading test. The dose of Mg to be administered is 5 mg/kg/day for at least 1 month. At this physiological dose level, oral magnesium supplement is totally devoid of the pharmacodynamic effects of parenteral magnesium. Correction of symptoms by this oral Mg load constitutes the best proof that they were due to Mg deficiency and may represent the beginning of its treatment. 1,4,10
Psychiatric forms of Mg deficiency have been well identified. Personality disorders are of the neurotic type. For example the Minnesota Multiphasic Personality Inventory (MMPI) finds a direct correlation between the "neurotic triad" (hypochondria, depression, and hysteria) and the EMG marks of NHE due to Mg deficiency.1,4 With all the psychometric evaluations, and with the DSM III R interview particularly, the clinical pattern induced through Mg deficiency was always neurotic (for example: generalized anxiety, panic attack disorders, and depression) but never psychotic. Mg deficiency never induces dementia.1,4,25,26 Although a neurosis pattern due to Mg deficiency is frequently observed and simply cured through oral physiological supplementation, neuroses are preeminently conditioning factors for stress. Neuroses may therefore very frequently produce secondary Mg depletion. They require their own specific antineurotic treatment and not mere oral Mg physiological supplementation, but both genuine forms of neurosis due to primary neural Mg deficiency and Mg depletion secondary to a neurosis may exist. These two conditions may be concomitant and reinforce each other. In these stressful patients it may be difficult to establish the primacy of one or the other. In practice, physiological oral Mg supplements may be added to psychiatric treatments, at least at the start.1,10
It is imperative to emphasize that the nervous consequences of Mg deficiency remain functional with anatomical integrity for a long time. They are completely reversible since they can be restored to normal with simple oral physiological Mg supplementation,1,5,10 but it should also be pointed out that a prolongation of untreated chronic Mg deficiency can produce irreversible lesions1,5 with histological changes: morphological changes in the rat hippocampus, degeneration of the Purkinje cells, glial aberration of positive Gomori cells, and neurovasculitis. When Mg deficiency secondary to alcoholism was corrected, no alcoholic encephalopathy was observed within a period of 5 years.1,5 These processes could account for the clinical and paraclinical data that persist after treatment of NHE due to Mg deficiency.1,5 They are especially of concern during the early development of the nervous system. The constitutional characteristics of the nervous forms of primary chronic Mg deficiency could arise from undetected maternal Mg deficiency.1,5 An early maternal Mg deficiency could be the fountainhead of more severe impairments: sudden infant death syndrome8,28 some forms of infantile convulsions or psychiatric disturbances,1,5 and even in adults, cardiovascular diseases and noninsulin-dependent diabetes mellitus.28 The protocol of the multicenter trials of maternal Mg physiological supplementation should be followed not only on the mother, the fetus, and the neonate, but also on the child throughout life from infancy to older age.28
Although Mg deficiency might not result in dementia, some types of Mg depletion can play a role in the physiopathology of several types of dementia.
Various types of more or less severe Mg depletion are used: genetic models (in rats and mice) and acquired models: either secondary to an irreversible (or partially reversible) cause (such as traumatic brain injury) or reversible. In the latter case, the models associate a low Mg intake with diverse types of Mg stress.10,22,23 Two types of experimental Mg depletions will be highlighted because of their possible link with dementia.
Garden soil and drinking water in some Western Pacific areas with high incidence of amyotrophic lateral sclerosis and parkinsonism-dementia (ALS-PD) contain high concentrations of polluting metals such as Al, Fe, and Mn, and low concentrations of common metals such as Mg and Ca. Decreased exposure to traditional sources of foodstuffs and drinking water resulted in a dramatic decline in ALS-PD.
These data as well as the links between aluminum load, magnesium status, and dialysis encephalopathy -- more hypothetically, Alzheimer's disease -- highlight the interest of corresponding experimental studies. With a high Al diet alone, Al content in the nervous system in rats showed no difference with a control group although serum Al was high. No degenerative process was observed. However, with an insufficient intake of Mg the same Al load induced an increase in Al and Ca concentrations in the nervous system and neurodegeneration with precipitation of insoluble hydroxyapatites.28
Hippocampal injury of ageing may originate from an increased calcium influx in pyramidal neurones resulting from the deleterious effects of increased release of excitatory aminoacids associated with a decrease of neuroprotective factors. Kainic acid acting through its specific receptors generates toxicity in the hippocampus, whereas Mg deficiency - a model of accelerated ageing - decreases Mg neuroprotection.23 In this model physiological Mg supplementation and pharmacological doses of Na acetyltaurinate were ineffective. On the other hand, Mg acetyltaurinate at pharmacological doses had preventive and curative effects in both the short and long terms.23
These two types of experimental Mg depletion models may be useful for screening various treatments of psychiatric disturbances possibly linked with Al load and ageing insults.21,23,29
Established links between some types of dementias and Mg depletion are presently scarce, but the experimental models of two types of Mg depletion, perhaps related to the physiopathology of some dementias, constitute promising tests for screening potentially efficient drugs both in these Mg depletions and in the related types of dementias.
It seems obvious to contrast the specific, easy, and efficient treatment of the nervous form of Mg deficiency with the difficult problems set by the treatment of certain types of Mg depletion playing a possible role in the physiopathology of some dementias.
Physiological oral Mg supplementation (5 mg/kg/day) is simple and can be carried out in the diet or with Mg salts. To correct in vivo experimental or clinical Mg deficiency all Mg salts have a comparable bioavailability, but evidently their anions have their own importance. This treatment is totally atoxic since it palliates Mg deficiency by simply normalizing the Mg intake.1,10 It is able to cure all the functional symptoms of Mg deficiency: signs of neuromuscular hyperexcitability and psychiatric symptoms which frequently mimic a neurotic pattern. It prevents irreversible stigmata of NHE due to primary or secondary magnesium deficiency, alcoholic encephalopathy in chronic alcoholism particularly.1,5 It is necessary to highlight the curative and preventive importance of oral physiological maternal Mg supplementation, not only during pregnancy but also in the child throughout life from infancy to older age, to possibly prevent the so-called constitutional factor of neurolability, some cases of sudden infant death syndrome, infantile convulsions, or psychiatric diseases, and even in adult cardiovascular diseases and noninsulin-dependent diabetes mellitus.1,5,8,10,28
With perhaps the one exception of the treatment of autism through very high pharmacological doses of vitamin B6 and high doses of Mg1,5,10,25,30 we cannot presently control the dysregulations of Mg status in Alzheimer's disease, dialysis encephalopathy, and ALS-PD. We can only advise some prophylactic measures. However, if an insufficient Mg intake (i.e., Mg deficiency) would add up to depletion cases, then an Mg deficit would be observed associating deficiency and depletion. The correction of Mg deficiency through simple oral supplementation therefore constitutes an adjuvant treatment of this possible component of Mg deficit.1,10
In some cases, the interest of pharmacological Mg therapy may be discussed. However, pharmacological Mg therapy may induce toxicity since it creates Mg overload. High oral doses of Mg (10 mg/kg/day) are advisable for chronic indications and the parenteral route is suitable for acute indications. Mg infusions can only be envisaged in intensive care units with careful monitoring of pulse, blood pressure, deep tendon reflexes, hourly diuresis, and electrocardiogram and respiratory recordings. It is presently difficult to evaluate the chronic toxicity of long-term high oral Mg doses: they may bring latent complications which may reduce life span.1,10 Neuromuscular hypoexcitability due to hypermagnesemia only occurs when plasma Mg is more than twice normal levels. The blood-brain barrier gives priority to the peripheral action of Mg overload.1,10 In vivo, this neuroprotection seems essentially indirect through the beneficial effects on antithrombotic platelet and endothelial functions and on vasospasm, mainly by acting as a calcium antagonist.1,9,10 Except for a pathological disruption of the blood-brain barrier, direct neuroprotection is observed with massively increased plasma Mg which cannot be practically carried out in human beings.10 In experimental models, the best protective effects with pharmacological doses of Mg were obtained with Mg acetyltaurinate, an Mg salt of the N-acetylamino-derived compound from taurine, the most neuroprotective inhibitory aminoacid.21,23 Further study should evaluate its clinical therapeutic effects.
Two different types of links between Mg deficit and the nervous system should be emphasized.
1 . NHE due to Mg deficiency with neuromuscular and psychiatric symptoms is well recognized nowadays. Induced by insufficient Mg intake, the primary or secondary acute or chronic nervous forms of Mg deficiency remain reversible over a long period by simply normalizing the Mg intake. Untreated chronic forms may however bring about irreversible organic disorders. The psychiatric forms of Mg deficiency may fit into a neurotic pattern, but never result in dementia.
2. In contrast, the relationships between some types of Mg depletion due to various dysregulations of Mg status and some dementias have not been clearly defined yet. However, some epidemiological, experimental and clinical data are promising and new paths remain open in this very interesting field of neuroscience research.
1. Durlach J: Magnesium in clinical practice. London-Paris, John Libbey Eurotext, 1988, pp.360.
2. Depoortere H., Francon D., and Llopis J.: Effects of a magnesium deficient diet on sleep in rats. Neuropsychobiology, 1993; 27:237-245.
3. Goto Y, Nakamura M, Abe S, et al: Physiological correlates of abnormal behaviors in magnesium-deficient rats. Epilepsy Res., 1993; 15:81-89.
4. Sandrini G, Ruiz G, Alfonsi E, et al: Effects of Mg salt administration on skin conductance response in neuronal hyperexcitability syndrome. Magnesium Res., 1989; 1/2:122-123.
5. Durlach J, Poenaru S, Rouhani S, et at: The control of central neural hyperexcitability in magnesium deficiency. In: Nutrients and Brain Function, Ed., W.B. Essmann, Basel, Karger, 1987, pp 49-71.
6. Poenaru S, Aymard P, Durlach J, et al: Regional distribution of magnesium in normal and Mg deficient rats (abst.). Magnesium Res., 1991; 4:246.
7. Lerma A, Planells E, Aranda P, et al: Evolution of Mg deficiency in rats. Ann. Nutr. Metabol., 1993; 37:210-217.
8. Durlach J, Durlach V, Rayssiguier Y, et al: Magnesium and thermoregulation. I. Newborn and infant. Is sudden infant death syndrome a Mg-dependent disease of the transition from chemical to physical thermoregulation? Magnesium Res., 1991; 4:137-152.
9. Kemp PA, Gardiner SM, March JE, et at: Effects of N6-nitro-l arginine methyl ester on regional haemodynamic responses to MGSO4 in conscious rats. J. Pharmacol., 1994; 111:325-331.
10. Durlach J, Durlach V, Bac P, et al: Magnesium and therapeutics. Magnesium Res., 1994; 7:313-328.
11. Weglicki WB, Tong Mak I, and Phillips TM: Blockade of cardiac inflammation in Mg2+ deficiency by substance P receptors inhibition. Circ. Res., 1994; 74 1009-1013.
12. Rayssiguier Y, Mazur A, Gueux E, et al: Mg deficiency affects lipid metabolism and atherosclerosis processes by a mechanism involving inflammation and oxidative stress (abst.). Magnesium Res., 1994; 7 (Supp. 1): 46-47.
13. Rayssiguier Y, Gueux E, Bussière L, et al: Dietary Mg affects susceptibility of lipoproteins and tissue to peroxidation in rats. J. Am. Coll. Nutr., 1993; 12:133-137.
14. Rayssiguier Y, Durlach J, Gueux E, et al: Mg and ageing. I. Experimental data: importance of oxidative damage. Magnesium Res., 1993; 6:369-378.
15. Stafford RE, Mak IT, Kramer JH, et al: Protein oxidation in Mg deficient rat brains and kidneys. Biochem. Biophys. Res. Commun., 1993; 196:596-600.
16. Smalheiser NR and Swanson DR,: Assessing a gap in the biomedical literature: Mg deficiency and neurologic disease. Neurosci. Res. Commun., 1994; 15:1-9.
17. Nakamura M, Abe S, Goto Y, et al: in vivo assessment of prevention of white-noise-induced seizure in Mg-deficient rats by NMDA receptor blockers. Epilepsy Res., 1994; 17: 249-256.
18. Nakamura M, Abe S, and Akazawa K: AMPA - but not NMDA - receptor blocker NBQX prevents seizure induction in Mg-deficient rats. Magnesium Res., 1995; 8:55-56.
19. Rayssiguier Y, Malpuech C, Nowacki W, et al: Evaluation of the inflammatory state during Mg deficiency in the rat (abst.). Magnesium Res., 1994; 7 (Supp. 1): 51.
20. Benyhe S, Szucs M, Varga E, et al: Cation and guanine nucleotide effects on ligand bindings properties of mu and delta receptors in rat brain membranes. Acta Biochim. Biophys. Hung., 1989; 24:69-8 1.
21. Durlach J, Durlach V, Bac P, et al: Mg and ageing. II. Clinical data: aetiological mechanisms and physiopathological consequences of Mg deficit in the elderly. Magnesium Res., 1993; 6 374-394.
22. Bac P, Herrenknecht C, Binet P, et al: Audiogenic seizures in Mg-deficient mice: effects of Mg pyrrolidone-2carboxylate, Mg acetyltaurinate, Mg chloride and vitamin B6. Magnesium Res., 1993; 6:11-19.
23. Bac P, Herrenknecht C, Binet P, et al: Effects of various Mg salts on the action of systemic kainic acid in Mg deficient rats: a new model of accelerated hippocampal ageing-like injury? (abst.). Magnesium Res., 1993; 6:300-301.
24. Velloso A: Magnesium, free radicals and longevity. Magnesium Res., 1994; 7 (Supp. 1): 48.
25. Galland L: Magnesium, stress and neuropsychiatric disorders. Magnesium Trace Elem., 1991-1992; 10:287-301,
26. Kirov GK, Birch NJ, Steadman P, et al: Plasma Mg levels in a population of psychiatric patients: correlation with symptoms. Neuropsychobiology, 1994; 30:73-78.
27. Durlach J: Death from infancy to older age and marginal Mg deficiency. How long should follow-up of the consequences of undernutrition in pregnancy be continued? Magnesium Res., 1993; 6:297-298.
28. Mitani K: Relationship between neurological diseases due to Al load, especially amyotrophic lateral sclerosis and magnesium status. Magnesium Res., 1992; 5:203-213.
29. Durlach J: Magnesium depletion and pathogenesis of Alzheimer's disease. Magnesium Res., 1990; 3:217-218.
30. Tolbert L, Haigler T, Waits M, et al: Brief report: lack of response in an autistic population to a low dose clinical trial of pyridoxine plus magnesium. J. Autism Dev. Dis., 1993; 23:193-199.
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